ABSTRACT We plan to complete our ongoing pilot vaccine trial in patients with World Health Organization (WHO) grade II low-grade gliomas (LGGs). The study was initially funded by an NCI SPORE grant, which is ending by August 2018. To address marked heterogeneity of genetics and protein expression in LGGs, we plan to target 10 non-mutated, but well- characterized and highly immunogenic, glioma-associated antigen (GAA) peptide epitopes (IMA950 vaccine). Furthermore, to induce robust IMA950-reactive T-cell responses, we will evaluate varlilumab, a novel agonistic monoclonal antibody (mAb) against CD27. Varlilumab activates human CD27+ T-cells only when T-cells are engaged with a human leukocyte antigen (HLA)-peptide complex through T-cell receptor (TCR), and mediates anti-tumor effects in preclinical tumor models. A recent, first-in-human phase I study showed tolerability, robust T-cell stimulation, and induction of the chemokine CXCL10. Our regimen also integrates poly:ICLC, which we have shown effectively induces expression of CXCL10 in glioma and very late activation antigen (VLA)-4 on vaccine-reactive T-cells, thereby promoting their homing to gliomas. Lastly, the effect of immunotherapy on the tumor microenvironment (TME) needs to be evaluated properly. Sampling of recurrent tumors after immunotherapy failure is not ideal due to the inconsistency in the timing of sampling among the patients and the potential for acquired resistance. Our study will solve this issue by treating patients pre-surgically, so that we will prospectively procure tumor samples. In our proposed study, patients who are clinically indicated for surgical resection of LGG are randomized to receive the IMA950+poly:ICLC vaccine plus varlilumab (Arm 1) or the IMA950+poly:ICLC vaccine alone (Arm 2) before surgical resection. After surgery, the patients will resume the same treatment regimen as they received prior to the surgery. The primary endpoint of the trial is to assess the safety and whether varlilumab enhances vaccine-reactive cytotoxic T-lymphocyte (CTL) responses in peripheral blood mononuclear cells (PBMC). The study also allows for prospective evaluation on the immunological impact of the regimen in resected tumors. Our overall hypothesis is that addition of agonist anti-CD27 mAb varlilumab will safely enhance induction and glioma-infiltration of IMA950 vaccine-reactive effector T-cells in LGG patients. The two Specific Aims are: Aim 1. Determine whether the combination of varlilumab, IMA950 and poly:ICLC is safe in patients with WHO grade II LGG. We will evaluate the incidence and severity of adverse events (AEs) associated with the treatment regime, with an early stopping rule based on the frequency of Regimen Limiting Toxicity (RLT). Aim 2. Determine whether varlilumab promotes IMA950-specific T-cell responses in PBMC and tumor. Leveraging tumor samples obtained following the pre-surgical immunotherapy and PBMC samples obtained at serial time points, we will determine whether addition of varlilumab (Arm 1) will enhance the induction of IMA950-reactive T-cells in PBMC as well as glioma-infiltrating lymphocytes. If successful, this study will establish a strong foundation for safety and biological activity of this regimen, and will allow us to design a large-scale study with clinical benefits as the primary objective.